Predictors of Invasive Adenocarcinomas Among Pure Ground-Glass Nodules Less Than 2 Cm in Diameter

Article Predictors of Invasive Adenocarcinomas among Pure Ground-Glass Nodules Less Than 2 cm in Diameter

Wen-Chi Hsu 1, Pei-Ching Huang 1, Kuang-Tse Pan 1, Wen-Yu Chuang 2 , Ching-Yang Wu 3 , Ho-Fai Wong 1, Cheng-Ta Yang 4 and Yung-Liang Wan 1,*

1 Department of Medical Imaging and Intervention, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; [email protected] (W.-C.H.); [email protected] (P.-C.H.); [email protected] (K.-T.P.); [email protected] (H.-F.W.) 2 Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; [email protected] 3 Division of Thoracic and Cardiovascular Surgery, Linkou Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; [email protected] 4 Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; [email protected] * Correspondence: [email protected]; Tel.: +886-3-3281200 (ext. 2575)

Simple Summary: Benign lesions, atypical adenomatous hyperplasia, and malignancies such as adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma may

feature pure ground-glass nodules on chest CT images, and the prognosis of patients with invasive adenocarcinoma is worse than others. The early detection and adequate management of invasive

Citation: Hsu, W.-C.; Huang, P.-C.; adenocarcinoma is crucial, but the pathology diagnosis of small nodules is difficult to obtain without Pan, K.-T.; Chuang, W.-Y.; Wu, C.-Y.; surgery. Our study aimed to analyze the CT characteristics of pure ground-glass nodules <2 cm Wong, H.-F.; Yang, C.-T.; Wan, Y.-L. for the identification of invasive adenocarcinomas. A total of 181 nodules in 171 patients were Predictors of Invasive enrolled. The larger size, lobulation, and air cavity were significantly more common in invasive Adenocarcinomas among Pure adenocarcinoma. The air cavity is the significant predictor in multivariate analysis. In conclusion, the Ground-Glass Nodules Less Than 2 possibility of invasive adenocarcinoma is higher in a pure ground-glass nodules when it is associated cm in Diameter. Cancers 2021, 13, with a larger size, lobulation, and air cavity. 3945. https://doi.org/10.3390/ cancers13163945 Abstract: Benign lesions, atypical adenomatous hyperplasia (AAH), and malignancies such as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma Academic Editors: Giuseppe Broggi (IA) may feature a pure ground-glass nodule (pGGN) on a thin-slide computed tomography (CT) and Lucia Salvatorelli image. According to the World Health Organization (WHO) classification for lung cancer, the prognosis of patients with IA is worse than those with AIS and MIA. It is relatively risky to perform a Received: 30 June 2021 Accepted: 2 August 2021 core needle biopsy of a pGGN less than 2 cm to obtain a reliable pathological diagnosis. The early Published: 5 August 2021 and adequate management of patients with IA may provide a favorable prognosis. This study aimed to disclose suggestive signs of CT to accurately predict IA among the pGGNs. A total of 181 pGGNs

Publisher’s Note: MDPI stays neutral of less than 2 cm, in 171 patients who had preoperative CT-guided localization for surgical excision with regard to jurisdictional claims in of a lung nodule between December 2013 and August 2019, were enrolled. All had CT images of published maps and institutional affil- 0.625 mm slice thickness during CT-guided intervention to confirm that the nodules were purely iations. ground glass. The clinical data, CT images, and pathological reports of those 171 patients were reviewed. The CT findings of pGGNs including the location, the maximal diameter in the long axis (size-L), the maximal short axis diameter perpendicular to the size-L (size-S), and the mean value of long and short axis diameters (size-M), internal content, shape, interface, margin, lobulation, Copyright: © 2021 by the authors. spiculation, air cavity, vessel relationship, and pleural retraction were recorded and analyzed. The Licensee MDPI, Basel, Switzerland. final pathological diagnoses of the 181 pGGNs comprised 29 benign nodules, 14 AAHs, 25 AISs, This article is an open access article 55 MIAs, and 58 IAs. Statistical analysis showed that there were significant differences among distributed under the terms and the aforementioned five groups with respect to size-L, size-S, and size-M (p = 0.029, 0.043, 0.025, conditions of the Creative Commons respectively). In the univariate analysis, there were significant differences between the invasive Attribution (CC BY) license (https:// adenocarcinomas and the non-invasive adenocarcinomas with respect to the size-L, size-S, size-M, creativecommons.org/licenses/by/ lobulation, and air cavity (p = 0.009, 0.016, 0.008, 0.031, 0.004, respectively) between the invasive 4.0/).

Cancers 2021, 13, 3945. https://doi.org/10.3390/cancers13163945 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3945 2 of 12

adenocarcinomas and the non-invasive adenocarcinomas. The receiver operating characteristic (ROC) curve of size for discriminating invasive adenocarcinoma also revealed similar area under curve (AUC) values among size-L (0.620), size-S (0.614), and size-M (0.623). The cut-off value of 7 mm in size-M had a sensitivity of 50.0% and a specificity of 76.4% for detecting IAs. In the multivariate analysis, the presence of air cavity was a significant predictor of IA (p = 0.042). In conclusion, the possibility of IA is higher in a pGGN when it is associated with a larger size, lobulation, and air cavity. The air cavity is the significant predictor of IA.

Keywords: ground-glass nodule; CT; predictor; invasive adenocarcinoma; non-invasive adenocarcinoma; pre-invasive lesion

1. Introduction Lung cancer was the leading cause of cancer death worldwide in 2020, as well as the 1st and 3rd most common cancer in men and women, respectively. There were 2.2 million newly diagnosed cases and 1.7 million cancer deaths reported for lung cancer [1]. The National Lung Screening Trial (NLST) reported a reduction in lung cancer mortality with chest computed tomography (CT) screening in the participants with high cancer risk [2]. Since 2013, the Preventive Services Task Force (USPSTF) has recommended low-dose computed tomography for lung cancer screening [3]. With the increased application of chest CT for lung cancer screening, pure ground-glass nodules (pGGNs) were frequently found [4]. The cause of pGGN varied, including not only benign lesions such as focal interstitial fibrosis, infection, and inflammation, but also lung cancer and its precursors [5]. In 2011, the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) established a new categorization for adenocarcinoma of the lung, including preinvasive lesions with atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) [6]. AAH, AIS, MIA, and IA may feature pGGN [7,8]. With adequate surgical resection, the patients with AIS and MIA have 100% or near 100% disease-free survival [9–11], and those with localized IA were associated with a 5-year survival rate of 70–90% [12,13]. If left untreated, the median survival of early lung cancer is merely 13 months in patients with T1 disease [14]. Therefore, it is crucial to identify IA earlier for a better outcome. It is a technical challenge to perform a core needle biopsy for a pGGN < 2 cm [15,16]. Therefore, some investigators have tried to identify IAs or malignant nodules presenting as pGGNs. Some authors attempted to differentiate preinvasive adenocarcinomas from IAs that present as pGGNs [4,17–24], while others investigated the correlation between the pathological findings and nodules presenting as solid, part-solid and pGGNs [25,26]. Our study aimed to analyze the CT findings of pGGN < 2 cm and differentiate IA from non-IA (NIA) for the appropriate management of pGGNs.

2. Materials and Methods 2.1. Patient Selection This study was approved by the Institutional Review Board of Chang Gung Med- ical Foundation (IRB No: 202001934B0 issued on 9 November 2020) and in compliance with the Health Insurance Portability and Accountability Act. In a period of 69 months, from December 2013 to August 2019, patients who underwent preoperative CT-guided localization for lung nodule excision were retrospectively reviewed. The inclusion criteria were shown as follows: (1) pGGN with a mean diameter <20 mm. The mean diameter was deﬁned as the average of the long axis and short axis diameters, measured on a lung window CT image. (2) Slice thickness of 0.625 mm on non-enhanced chest CT. (3) The presence of deﬁnite pathological diagnoses. According to the inclusion and exclusion Cancers 2021, 13, x FOR PEER REVIEW 3 of 12

Cancers 2021, 13, 3945 3 of 12 CT image. (2) Slice thickness of 0.625 mm on non-enhanced chest CT. (3) The presence of definite pathological diagnoses. According to the inclusion and exclusion criteria shown criteriain the flowchart shown in in the Figure ﬂowchart 1, the in CT Figure images1, the with CT a imagesslice thickness with a slicegreater thickness than 0.625 greater mm thanand 0.625nodules mm with and solid nodules components with solid or components inconclusive or inconclusivepathological pathologicalresults were resultsall ex- werecluded. all excluded.Both benign Both and benign malignant andmalignant pGGNs were pGGNs included were in included this study. in this Finally, study. a Finally,total of a181 total nodules of 181 in nodules 171 patients in 171 patientswere enrolled were enrolledin this study. in this The study. clinical The clinicaldata of dataeach ofpatient each patientwere recorded; were recorded; these included these included age, gender, age, gender, smoking smoking history, history, drinking drinking history, history, cancer cancer his- history,tory, and and the the pathological pathological results results of ofthe the nodules. nodules.

FigureFigure 1.1. FlowchartFlowchart ofof patientpatient selection.selection. CT-guided:CT-guided: computedcomputed tomography-guided;tomography-guided; pGGNs:pGGNs: purepure ground-glassground-glass nodules;nodules; AAH:AAH: atypicalatypical adenomatousadenomatous hyperplasia;hyperplasia; AIS:AIS: adenocarcinomaadenocarcinoma inin situ;situ; MIA:MIA: minimallyminimally invasiveinvasive adenocarcinoma;adenocarcinoma; IA:IA: invasiveinvasive adenocarcinoma.adenocarcinoma.

2.2.2.2. CTCT ExaminationExamination PatientsPatients werewere referredreferred forfor preoperativepreoperative localizationlocalization byby thethe surgeon.surgeon. AllAll CT-guidedCT-guided localizationlocalization waswas performedperformed usingusing aa helicalhelical CTCT scannerscanner (BrightSpeed(BrightSpeed scannerscanner GEGE MedicalMedical Systems,Systems, Milwaukee,Milwaukee, WI, WI, USA). USA). The The scanning scanning parameters parameters of theof the non-enhanced non-enhanced chest chest CT areCT asare follows: as follows: (1) 120 (1) kVp,120 kVp, (2) 100–250 (2) 100–250 mA, (3) mA, beam (3) pitch,beam 0.875–1.675,pitch, 0.875–1.675, and (4) and reconstructed (4) recon- slicestructed thickness slice thickness of axial images, of axial including images, including 0.625 mm 0.625 and 5 mm mm. and The 5 imagemm. The with image 0.625 with mm slice0.625 thickness mm slice wasthickness used forwas nodule used for analysis. nodule analysis.

2.3.2.3. PurePure Ground-GlassGround-Glass NoduleNodule AnalysisAnalysis TwoTwo radiologists,radiologists, who who subspecialize subspecialize in in thoracic thoracic imaging imaging (with (with 7 years7 years and and 37 years37 years of experience,of experience, respectively), respectively), and and were were blinded blinded to theto the pathology pathology results results and and clinical clinical informa- infor- tion,mation, reviewed reviewed all the all nodulesthe nodules on the on axialthe axial images images with 0.625with 0.625 mm slice mm thickness,slice thickness, obtained ob- duringtained during the CT-guided the CT-guided localization. localization. The divergence The divergence in image in interpretation image interpretation was resolved was byre- consensus.solved by consensus. Both the mediastinal Both the mediastinal window (window window width/window (window width/window level = 350 HU/50 level = HU) 350 − andHU/50 lung HU) window and lung (window window width/window (window width/window level = 1500 level HU/ = 1500600 HU)HU/− were600 HU) used were for interpretation. Pure GGN was defined as a nodule with hazy opacity, which did not ob- used for interpretation. Pure GGN was defined as a nodule with hazy opacity, which did scure the underlying bronchial structures or pulmonary vessels under the lung window of not obscure the underlying bronchial structures or pulmonary vessels under the lung win- non-enhanced CT [27]. The CT findings of the lung nodules were recorded and measured dow of non-enhanced CT [27]. The CT findings of the lung nodules were recorded and as follows: location (upper lobe versus not upper lobe), size-L (the maximal diameter measured as follows: location (upper lobe versus not upper lobe), size-L (the maximal in the long axis), size-S (the maximal short-axis diameter perpendicular to the long axis diameter in the long axis), size-S (the maximal short-axis diameter perpendicular to the of size-L), size-M (the mean of long- and short-axis diameter), content (homogenous or long axis of size-L), size-M (the mean of long- and short-axis diameter), content (homog- heterogeneous), shape (oval, polygonal or irregular), interface (well-defined or ill-defined), enous or heterogeneous), shape (oval, polygonal or irregular), interface (well-defined or margin (smooth or coarse), lobulation, spiculation, air cavity, vessel relationship, and pleural retraction. Of the content, pGGNs were further categorized into homogenous or heterogeneous: the homogenous nodules had homogeneous opacities in the lung window,

Cancers 2021, 13, x FOR PEER REVIEW 4 of 12

Cancers 2021, 13, 3945 4 of 12 ill-defined), margin (smooth or coarse), lobulation, spiculation, air cavity, vessel relationship, and pleural retraction. Of the content, pGGNs were further categorized into homogenous or heterogeneous: the homogenous nodules had homogeneous opacities in the lung and the heterogeneous nodules had suspicious solid components, which were only identi- window, and the heterogeneous nodules had suspicious solid components, which were fied in the lung window but not in the mediastinal window [28]. Of the air cavity, both only identified in the lung window but not in the mediastinal window [28]. Of the air the vacuole sign and air–bronchogram were included, and the vacuole sign indicated tiny cavity, both the vacuole sign and air–bronchogram were included, and the vacuole sign points, with translucent and air-density shadows in the nodules. In terms of the vessel indicated tiny points, with translucent and air-density shadows in the nodules. In terms relationship, type I was defined as vessels passing by or passing through the nodule, and of the vessel relationship, type I was defined as vessels passing by or passing through the type II was defined as distorted, dilated or engorged vessels within the nodule [29]. The nodule, and type II was defined as distorted, dilated or engorged vessels within the nod- imaging findings of the nodule are shown in Figure2. ule [29]. The imaging findings of the nodule are shown in Figure 2.

Figure 2. The illustration of imaging characte characteristicristic of the pure ground-glass nodule (pGGN) on computed tomography images. (A) Atypical adenomatous hyperplasia (AAH) with homogenous content, oval shape, well-defined interface, and images. (A) Atypical adenomatous hyperplasia (AAH) with homogenous content, oval shape, well-defined interface, smooth margin. (B) Minimally invasive adenocarcinoma (MIA) with irregular shape and vessel passing through. (C,D) and smooth margin. (B) Minimally invasive adenocarcinoma (MIA) with irregular shape and vessel passing through. Invasive adenocarcinoma (IA) with heterogeneous content, showing suspicious solid component in the center of nodule in(C ,lungD) Invasive window adenocarcinoma (window width/window (IA) with level heterogeneous = 1500 HU/ content,−600 HU) showing in C but suspicious invisible in solid mediastinal component window in the (window center of width/windownodule in lung windowlevel = 350 (window HU/50 HU) width/window in D. (E) Necrotizing level = 1500 granulomatous HU/−600 HU) inflammation in C but invisible with the in mediastinalill-defined interface. window ((windowF) IA with width/window coarse margin leveland polygonal = 350 HU/50 in shape. HU) in (G D.) IA (E) with Necrotizing lobulation. granulomatous (H) MIA with inflammation spiculation. with(I) IA the adjacent ill-defined to a vesselinterface. with ( Fair-bronchogram) IA with coarse (black margin arrow) and polygonal in the nodule. in shape. (J) IA (withG) IA vacuole with lobulation. sign (black (arrow).H) MIA (K with) IA spiculation.with type II vessel (I) IA relationship,adjacent to a dilated vessel with vessel air-bronchogram (black arrow) within (black the arrow) nodule. in the (L nodule.) Adenocarcinoma (J) IA with in vacuole situ with sign pleural (black retraction. arrow). (K ) IA with type II vessel relationship, dilated vessel (black arrow) within the nodule. (L) Adenocarcinoma in situ with pleural retraction. 2.4. Pathological Diagnosis 2.4. PathologicalAll enrolled Diagnosis GGNs had a definite pathological diagnosis. Pathology results were clas- sifiedAll into enrolled five groups: GGNs AAH, had aAIS, definite MIA, pathological IA, and benign. diagnosis. The AAH, Pathology AIS, MIA, results and were IA were clas- basedsified intoon the five International groups: AAH, Association AIS, MIA, for IA, the and Study benign. of TheLung AAH, Cancer AIS, (IASLC)/American MIA, and IA were based on the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) Classification of Lung Adeno-

Cancers 2021, 13, 3945 5 of 12

carcinoma in Resection Specimens [6]. The benign group included the benign pathology result, except for AAH. Due to the worse prognosis of patients with IA, the benign lesions AAH, AIS, and MIA were designated as the NIA group.

2.5. Statistics Statistical analyses were performed using the SPSS software package (Version 20.0. Armonk, NY, USA: IBM Corp.). Quantitative variables were expressed as mean ± standard deviation. Categorical variables were expressed as numbers and percentages. A comparison was performed among the ﬁve pathology groups: Benign, AAH, AIS, MIA, and IA. The quantitative variables, including age and nodule size, were compared with the Kruskal–Wallis test. Differences in the categorical variables, the patients’ gender, smoking history, drinking history, cancer history, nodule location, content, shape, interface, margin, lobulation, spiculation, air cavity, vessel relationship, and pleural retraction were compared with the chi-square test or Fisher test. A comparison between IA and NIA groups was performed with the Mann–Whitney U test for quantitative variables, and the chi-square or Fisher test was used for categorical variables. The receiver operating characteristic (ROC) curve of nodule size was created to determine the cut-off value used to predict IA, and the area under curve (AUC) value was calculated. The Youden index was performed to decide the optimal cut-off point. In the multivariate analysis, the imaging features with a p-value < 0.05 were included in the logistic regression with a forward stepwise selection, which was used to determine the predictors for IA. A p-value < 0.05 was considered statistically signiﬁcant.

3. Results 3.1. Demographic Data and Nodule Information The age of 171 patients (129 females) ranged from 25 to 81 years old (mean age 55.0 years old). There were 14 AAHs, 25 AIS’s, 55 MIAs, and 58 IAs, and 29 nodules were benign, comprising fibrosis, chronic inflammation, localized organizing pneumonia, and necrotizing granulomatous inflammation (Table1). Ninety-eight (54.1%) nodules were located in the upper lobes. There was no significant difference among the five groups with respect to the demographic data, history of smoking, drinking and cancer, and the nodule location.

Table 1. Demographic data and nodule information.

Variables Benign AAH AIS MIA IA All p-Value Nodule Numbers 29 14 25 55 58 181 Age 55.8 ± 10.3 55.4 ± 12.2 55.1 ± 10.9 53.9 ± 11.6 55.4 ± 10.7 55.0 ± 11.0 0.956 Sex (Female) 21 (72.4) 10 (71.4) 16 (64.0) 37 (67.3) 45 (77.6) 129 (71.3) 0.695 Smoking history 2 (6.9) 1 (7.1) 2 (8.0) 8 (14.5) 2 (3.4) 15 (8.3) 0.318 Drinking history 2 (6.9) 1 (7.1) 1 (4.0) 2 (3.6) 2 (3.4) 8 (4.4) 0.833 Cancer history 5 (17.2) 1 (7.1) 3 (12.0) 18 (32.7) 14 (24.1) 41 (22.7) 0.122 Nodule Location 0.698 In upper lobe 15 (51.7) 9 (64.3) 16 (64.0) 27 (49.1) 31 (53.4) 98 (54.1) Not in upper lobe 14 (48.3) 5 (35.7) 9 (36.0) 28 (50.9) 27 (46.6) 83 (45.9) The numbers in parenthesis indicate percentage. AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma.

3.2. Imaging Characteristics Analysis Table2 shows the CT imaging findings of the five pathology groups. Among the five groups, there were significant differences with respect to the size-L, size-S, and size-M (p = 0.029, 0.043, and 0.025, respectively). The sign of spiculation was only found in three (5.5%) of the 55 MIAs and one (1.7%) of 58 IAs without statistical significance. No significant difference was found among the five groups with respect to the other imaging findings. However, there were significant differences between the IA and NIA groups with respect to the size-L, size-S, and size-M (8.2 ± 3.4 mm vs. 6.8 ± 2.7 mm in size-L, 6.2 ± 2.6 mm Cancers 2021, 13, 3945 6 of 12

vs. 5.2 ± 2.1 mm in size-S, and 7.2 ± 2.9 mm vs 6.0 ± 2.3 mm in size-M) with p-values of 0.009, 0.016, and 0.008, respectively (Table3). The receiver operating characteristic (ROC) curve of each of the size-L, size-S, and size-M showed an AUC value of 0.620, 0.614, and 0.623, respectively (Figure3). The cut-off value of 7.0 mm for size-M showed a sensitivity of 50.0% and a specificity of 76.4% in predicting IA. In terms of morphology, lobulation was significantly more prevalent in IA (6, 10.3%) than NIA (3, 2.4%), with a p-value of 0.031 (Table3). The air cavity within nodules was also more frequently observed in IA (24, 41.4%) than in NIA (26, 21.1%), with a p-value of 0.004 (Table3). In multivariate analysis with stepwise logistic regression, there was only one significant predictor for air cavity (odds ratio: 2.126; 95% confidence interval: 1.027–4.403, p = 0.042). The borderline p-value was shown in size-M (odds ratio: 1.146; 95% confidence interval: 0.999–1.315, p = 0.051) and lobulation (odds ratio: 4.382; 95% confidence interval: 0.981–19.583, p = 0.053).

Table 2. Analysis and comparison of computed tomographic ﬁndings.

Imaging Features Benign AAH AIS MIA IA p-Value Size-L 7.4 ± 3.0 6.3 ± 2.5 6.0 ± 1.9 7.1 ± 2.7 8.2 ± 3.4 0.029 * Size-S 5.6 ± 1.9 4.6 ± 1.7 5.0 ± 1.3 5.3 ± 2.5 6.2 ± 2.6 0.043 * Size-M 6.5 ± 2.4 5.4 ± 2.0 5.5 ± 1.5 6.2 ± 2.5 7.2 ± 2.9 0.025 * Content 0.643 Homogenous GGN 17 (58.6) 10 (71.4) 16 (64.0) 30 (54.5) 30 (51.7) Heterogeneous GGN 12 (41.4) 4 (28.6) 9 (36.0) 25 (45.5) 28 (48.3) Shape 0.203 Oval or polygonal 24 (82.8) 12 (85.7) 25 (100.0) 48 (87.3) 53 (91.4) Irregular 5 (17.2) 2 (14.3) 0 (0) 7 (12.7) 5 (8.6) Interface 0.100 Well-defined 23 (79.3) 13 (92.9) 24 (96.0) 53 (96.4) 51 (87.9) Ill-defined 6 (20.7) 1 (7.1) 1 (4.0) 2 (3.6) 7 (12.1) Margin 0.708 Smooth 25 (86.2) 12 (85.7) 20 (80.0) 43 (78.2) 43 (74.1) Coarse 4 (13.8) 2 (14.3) 5 (20.0) 12 (21.8) 15 (25.9) Lobulation 1 (3.4) 1 (7.1) 1 (4.0) 0 (0) 6 (10.3) 0.083 Spiculation 0 (0) 0 (0) 0 (0) 3 (5.5) 1 (1.7) 0.635 Air cavity 8 (27.6) 2 (14.3) 5 (20.0) 11 (20.0) 24 (41.4) 0.060 Vessel relationship 0.532 Type I 26 (89.7) 14 (100.0) 24 (96.0) 47 (85.5) 52 (89.7) Type II 3 (10.3) 0 (0) 1 (4.0) 8 (14.5) 6 (10.3) Pleural retraction 2 (6.9) 2 (14.3) 4 (16.0) 6 (10.9) 11 (19.0) 0.590 *: p-value < 0.05 with statistically significance. The numbers in parenthesis indicate percentage. AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma; size-L: the maximal diameter in the long axis; size-S: the maximal short axis diameter perpendicular to the long axis; size-M: the mean value of long and short axis diameters; GGN: ground-glass nodule. Type I vessel relationship was defined as vessels passing by or passing through the nodule; and type II was defined as distorted, dilated, or engorged vessels within the nodule [29].

Table 3. Univariate and multivariate analysis between the non-invasive adenocarcinoma (NIA) group and invasive adenocarcinoma (IA) group.

Univariate Multivariate Imaging Features NIA IA p-Value p-Value Size-L 6.8 ± 2.7 8.2 ± 3.4 0.009 * Size-S 5.2 ± 2.1 6.2 ± 2.6 0.016 * Size-M 6.0 ± 2.3 7.2 ± 2.9 0.008 * 0.051 Heterogeneous content 50 (40.7) 28 (48.3) 0.334 Irregular shape 14 (11.4) 5 (8.6) 0.572 Ill-deﬁned interface 10 (8.1) 7 (12.1) 0.397 Coarse margin 23 (18.7) 15 (25.9) 0.270 Lobulation 3 (2.4) 6 (10.3) 0.031 * 0.053 Cancers 2021, 13, x FOR PEER REVIEW 7 of 12

Size-L 6.8 ± 2.7 8.2 ± 3.4 0.009 * Size-S 5.2 ± 2.1 6.2 ± 2.6 0.016 * Size-M 6.0 ± 2.3 7.2 ± 2.9 0.008 * 0.051 Heterogeneous 50 (40.7) 28 (48.3) 0.334 content Cancers 2021, 13, 3945 Irregular shape 14 (11.4) 5 (8.6) 0.572 7 of 12 Ill-defined interface 10 (8.1) 7 (12.1) 0.397 Coarse margin 23 (18.7) 15 (25.9) 0.270 Table 3.LobulationCont. 3 (2.4) 6 (10.3) 0.031 * 0.053 Spiculation 3 (2.4) 1 (1.7) 1.000 Univariate Multivariate ImagingAir cavity Features 26 (21.1) NIA 24 (41.4) IA 0.004 * 0.042 * p-Value p-Value Type II vessel 12 (9.8) 6 (10.3) 0.117 relationshipSpiculation 3 (2.4) 1 (1.7) 1.000 Air cavity 26 (21.1) 24 (41.4) 0.004 * 0.042 * Pleural retraction 14 (11.4) 11 (19.0) 0.168 Type II vessel 12 (9.8) 6 (10.3) 0.117 *: p-valuerelationship < 0.05 with statistically significance. The numbers in parenthesis indicate percentage. NIA: non-invasivePleural retraction adenocarcinoma 14s; (11.4)all benign lesions, 11 (19.0) atypical adenomatous 0.168 hyperplasia, adeno- *:carcinomap-value < 0.05 in situ, with statisticallyand minimally signiﬁcance. invasive The adenocar numberscinoma in parenthesis are classified indicate percentage. to NIA; IA: NIA: invasive non-invasive ade- adenocarcinomas;nocarcinoma; size-L: all benign the maximal lesions, atypical diameter adenomatous in the long hyperplasia, axis; size-S: adenocarcinoma the maximal in short situ, andaxis minimally diame- invasiveter perpendicular adenocarcinoma to the are long classiﬁed axis; tosize-M: NIA; IA: the invasive mean value adenocarcinoma; of long and size-L: short the axis maximal diameters; diameter GGN: in the longground-glass axis; size-S: nodule. the maximal short axis diameter perpendicular to the long axis; size-M: the mean value of long and short axis diameters; GGN: ground-glass nodule.

Figure 3. The receiver operating characteristic (ROC)(ROC) curvescurves ofof size-L,size-L, size-S,size-S, andand size-Msize-M inin discrimi-discrim- natinginating invasive invasiveadenocarcinoma adenocarcinoma fromfrom otherother pathologicalpathological results,results, withwith thethe areaarea underunder curvecurve (AUC)(AUC) valuesvalues ofof 0.620,0.620, 0.614,0.614, andand 0.623,0.623, respectively. Size-L:Size-L: thethe maximalmaximal diameterdiameter in the long axis; size-S: thethe maximalmaximal short-axisshort-axis diameter diameter perpendicular perpendicular to to the the long long axis axis of of nodule; nodule; size-M: size-M: the the mean mean value value of longof long and and short short axis axis diameters. diameters.

4. Discussion ItIt maymay bebe relativelyrelatively difficultdifficult toto obtainobtain aa definitedefinite pathologicalpathological diagnosisdiagnosis ofof pGGNpGGN lessless thanthan 2020 mmmm duedue toto the technical challenges andand potentialpotential risksrisks ofof complicationscomplications forfor pGGNpGGN whenwhen performing core core needle needle biopsy biopsy [15,16]. [15,16 ].The The imaging imaging features features may may play play a crucial a crucial role rolein differentiating in differentiating benign benign and malignant and malignant nodules. nodules. In Lung-RADS In Lung-RADS 1.1, recommended 1.1, recommended by the by the American College of Radiology (ACR), a pGGN of less than 30 mm is designated as negative. However, Kastner et al. reported that the increase in the allowable nodule size for pGGNs in category 2 from 20 mm (version 1.0) to 30 mm (version 1.1) showed no benefit, and one of the three down-categorized GGNs (version 1.1) was proved to be malignant (false-negative finding) [30]. In addition, the pGGNs classified into categories 2 or 3, based on Lung-RADS 1.1, were reported to have a higher malignancy rate than expected [31]. Therefore, it is worth investigating the imaging features to differentiate IA and NIA featuring a pGGN of less than 20 mm in diameter. Cancers 2021, 13, 3945 8 of 12

Benign GGNs were not included in studies that attempted to differentiate IA from pre-invasive lesions [4,17–24]. Some reports analyzed the differentiation of benign and malignant nodules that were solid, part-solid and GGN [25,26]. Our study aimed to investigate the potential predictors for differentiating IA from NIA, which featured a pGGN of less than 20 mm in diameter. In our study, there were significant differences among the five pathology groups (benign, AAH, AIS, MIA, and IA) with respect to size-L, size-S, and size-M. In comparison with NIA, IA had a significantly larger size-L, size-S, and size-M. The lobulation and air cavity were significantly more prevalent in IA than in NIA. Our multivariate analysis showed that the air cavity was a significant predictor of IA. The correlation between nodule size and malignancy was frequently investigated. In the NELSON study, the probability of lung cancer was 0.4% for nodules smaller than 5 mm in diameter, and the malignancy rate was raised to 16.9% for nodules larger than 10 mm [32]. In the study based on the database of NSLT, the malignancy rate for GGNs with a size ranging from 10 to 19 mm was 6%, which is higher than 1.3% for GGN < 10 mm [31]. Qi et al. reported that the cut-off value of 11.5 mm for pGGNs ≤ 30 mm had a sensitivity of 75% and a specificity of 91.8% in identifying invasive adenocarcinoma among pGGNs [33]. Jin et al. reported that the optimal cut-off value of 10.5 mm had a sensitivity of 86.30% and a specificity of 61.90% in the differentiation of invasive and pre-invasive lesions [23]. In our study, there were significant differences in diameter among the five pathology groups and between the NIA and IA. The ROC curves of the size-L, size-S, and size-M were created with similar AUC values but associated with the highest figure of 0.623 for size-M in comparison with the 0.620 for size-L and 0.614 for size-S. The cut-off value of 7 mm in mean diameter showed a sensitivity of 50.0% and a specificity of 76.4% in differentiating NIA and IA. The difference in cut-off points and diagnostic accuracy in different series could be attributed to differences in the methods and materials, and further research in a larger sample size may be needed. The findings in previous reports and our results suggested the significance of size in the management of GGNs. The mean diameter of the long axis and short axis was recommended for the assessment of small nodules (<10 mm) by the Fleischner Society [34], and for the measurement of all nodules according to the Lung-RADS 1.1. Therefore, the measurement of both a long- and short-axis diameter is crucial for nodule evaluation. Several studies discussed the CT morphology of the lung nodules, including the lobulation, spiculation, air-bronchogram, and vacuole sign [35–38]. Furuya et al. reported that 82% of the lobulated nodules and 97% of the spiculated nodules were malignant [39]. The lobulation and spiculation of pGGN were also more common in invasive lesions (IA and MIA) than in preinvasive lesions [4]. The lobulation is associated with more EGFR mutation in adenocarcinoma than the wild-type EGFR [40]. In our research, lobulation was more frequently found in IA (10.3%) than NIA (2.4%), with statistical significance (p = 0.031). However, there was no significant difference among the five pathology groups and between the IA and NIA with respect to spiculation. Nevertheless, the spiculation was only observed in MIA (3, 5.5%) and IA (1, 1.7%), and none was observed in the benign lesions, AAH, and AIS. The non-significance of spiculation in our study could probably be attributed to the limited number of spiculated nodules. The air cavity, including air-bronchogram or vacuole, as seen in our study, was another CT characteristic related to malignancy. The air cavities are more commonly found in malignant rather than benign GGNs, and air-bronchograms are more frequently demonstrated in IA than in AIS [41,42]. In our study, the prevalence of the air cavity was higher in IA (24, 41.4%) than in NIA (26, 21.1%), with a p-value of 0.004. In our multivariate analysis, air cavity, size-M, and lobulation are significant or borderline significant predictors for IA, with a p-value of 0.042, 0.051, and 0.053, respectively. In our study, the air cavity in the nodules was found in 41.4% of IAs, and a total of 78.9% of NIA did not feature an air cavity; these findings are similar to those of another study, with a sensitivity of 53.7% and a specificity of 86.7% in differentiating malignancy from benignity among a total of Cancers 2021, 13, 3945 9 of 12

112 GGOs [41]. For usefulness in daily clinical practice, further investigation with a larger sample size and a better diagnostic performance may be required. In terms of nodule content, Jin et al. classified the uniformity of ground-glass nodules into three categories, namely homogenous, less homogenous, and heterogeneous [23]. There were significant differences in the uniformity between preinvasive lesions and MIAs or invasive adenocarcinomas (p = 0.01, p < 0.05). Their study included 94 pGGNs, comprising 21 preinvasive lesions, 35 MIAs, and 38 IAs, but excluded benign nodules, except for AAHs. Chu et al. reported that invasive pGGNs (MIAs and IAs) were significantly more likely to be heterogeneous in density than preinvasive lesions (p < 0.05). Their study enrolled 172 pGGNs, including 14 AAHs, 59 AISs, 68 MIAs, and 31 IAs [4]. In our study, the prevalence of heterogeneous content was associated with a positive correlation with the nodule invasiveness, shown as follows: in AAH (28.6%), AIS (36.0%), MIA (45.5%), and IA (48.3%). However, heterogeneous attenuation was found in 41.4% of our benign pGGNs. The inclusion of all benign pGGNs in our research probably led to the statistical insignificance in our result. The classification of nodule content or uniformity may differ in different studies. According to the consensus statement by the Fleischner Society [27], the ground-glass opacity on CT scans appears as hazy increased opacity of the lung, with preservation of the bronchial and vascular margins. The standard in identifying solid components, which obliterated the bronchial and vascular margins, could be different in different readers [43]. Similarly, variance may exist in the assessment of the nodule content in our work. Therefore, both lung and mediastinal windows were applied in our study for identifying pGGNs and assessing the uniformity of nodule content. In addition, the slice thickness varied in different studies, which may influence the recognition of the nodule components. The difference in methods and materials used in classifying nodule content may affect the result of comparison among the nodules with different pathological diagnoses. There was no significant difference among the five pathology groups and between IA and NIA with respect to other imaging characteristics: shape, interface, margin, spiculation, vessel relationship, and pleural retraction. This may be partly elucidated by the fact that these features are neither easily found nor strong discriminators in pGGNs < 20 mm. There are several limitations in this study. First, selection bias could not be avoided in our study. Not all of the patients who underwent surgical excision of GGNs < 2 cm were included. For an optimal evaluation of the morphology of ground-glass nodules, images with a slice thickness of 0.625 mm was one of the inclusion criteria in this retrospective study. The 0.625 mm slice thickness images were obtained on the day of CT-guided localization before surgery. Applying slice thickness of 0.625 mm for evaluating lung nodule in the regular follow-up CT is less practical. Though not all patients who underwent surgery were included in this study, the prevalence of malignancy was 76.2% (138/181) in our study, which is consistent with that of 78% in another report [44]. Second, this is a retrospective cross-sectional study. The longitudinal study with evaluation of nodules’ growth was not performed in this work. Third, the imaging features of pGGNs were interpreted by two radiologists, who reached a consensus without analysis of inter-observer variability. Lastly, this study was based on a single center, and the sample size was rather small. Further study with more cases is required to validate our results.

5. Conclusions The possibility of IA is higher in a pGGN when it is associated with a larger size, lobulation, and air cavity. The air cavity is a signiﬁcant predictor of IA.

Author Contributions: Conceptualization, Y.-L.W. and W.-C.H.; formal analysis, Y.-L.W., K.-T.P., and P.-C.H.; investigation, K.-T.P., P.-C.H., W.-Y.C., and C.-Y.W.; methodology, C.-T.Y. and H.-F.W.; resources, C.-Y.W. and Y.-L.W.; supervision: C.-T.Y. and Y.-L.W.; validation: W.-Y.C. and C.-Y.W.; writing—original draft, W.-C.H. and P.-C.H.; writing—review and editing, Y.-L.W., W.-C.H., and H.-F.W. All authors have read and agreed to the published version of the manuscript. Cancers 2021, 13, 3945 10 of 12

Funding: This study was sponsored by a grant from the Chang Gung Medical Foundation grant number BMRP193. Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Chang Gung Medical Foundation with IRB No. 202001934B0 on 9 November 2020. Informed Consent Statement: Patient consent was waived due to the ethical approval stating that no consent to participate was required for this study, which was a retrospective research using existing data in our electronic chart and imaging system. Data Availability Statement: The data presented in this study are stored in our institutional reposi- tory and will be shared on request from the corresponding author. Conﬂicts of Interest: The authors declared no conﬂict of interest.

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